A missense point mutation in COL10A1 identified with whole-genome deep sequencing in a 7-generation Pakistan dwarf family

Abstract

Disease-associated variants in the human genome are continually being identified using DNA sequencing technologies that are especially effective for Mendelian disorders. Here we sequenced whole genome to high coverage (>30×) of 6 members of a 7-generation family with dwarfism from a consanguineous tribe in Pakistan to determine the causal variant(s). We identified a missense variant rs111033552 (c.2011T>C [p.Ser671Pro]) located in COL10A1 (encodes the alpha chain of type X collagen) as the most likely contributor to the dwarfism. We further confirmed the variant in 22 family members using Sanger sequencing. All affected individuals are heterozygous for the missense mutation rs111033552 and no individual homozygous was observed. Moreover, the mutation was absent in 69,985 individuals representing >150 global populations. Taking advantage of whole-genome sequencing data, we also examined other variant forms, including copy number variation and insertion/deletion, but failed to identify such variants enriched in the affected individuals. Thus rs111033552 had priority for linkage with dwarfism.

PGG.SNV: understanding the evolutionary and medical implications of human single nucleotide variations in diverse populations

“…Recently, an increased number of researchers investigate the allele frequency of variants in human populations and predict functional impacts or causality for each variant according to an allele’s rareness in medical studies [7, 36–38]. Though there has been a dramatic increase in the number of genomes sequenced for diverse human populations, most population prevalence annotation tools [87, 97] are frequently based on a few number of data sets, especially on 1KGP [4] and gnomAD [39], which are absolutely valuable reference panels.…”

“…Moreover, by leveraging the laws of intra-species micro-evolution, analysis of the population prevalence of variants has increased dramatically in medical studies and functional genomics [36, 37]. Specifically, researchers are able to retrieve the allele frequency of a variant and predict the impact of that variant according to its rareness, as deleterious alleles are generally assumed to show lower frequencies in a population than benign alleles [38]. The two most-frequently used data sets for this are the 1000 Genomes Project (1KGP) [4] and the Genome Aggregation Database (gnomAD) [39].…”

Natural Mutations Affect Structure and Function of gC1q Domain of Otolin-1

“…In the case of adiponectin, R112C and I164T are examples of variants, which impair trimerization of adiponectin and secretion of the protein into circulation, which leads to reduced adiponectin levels and ultimately to a diabetic phenotype [9]. In the case of collagen X, various mutations in the gC1q domain (conventionally called NC1 for collagens) are associated with Schmid metaphyseal chondrodysplasia (spondylometaphyseal dysplasia), a rare genetic disease characterized by short stature, long bone growth abnormalities and waddling gait [10][11][12][13]. S163R variant of C1QTNF5 is involved in pathogenesis of late-onset retinal macular degeneration due to the weakening of the intracellular connections in RPE mediated by C1QTNF5.…”

Schmid Metaphyseal Chondrodysplasia

“…Homozygotes. Biallelic pathogenic variants in COL10A1 have been associated with a more severe phenotype [Ain et al 2018] and in some cases embryonic lethality [Zhang et al 2018].…”

“…The proportion of cases caused by a de novo pathogenic variant is unknown. • Some individuals diagnosed with SMCD have an affected parent [Ikegawa et al 1998, Hasegawa et al 2015, Zhang et al 2018. The heterozygous parent almost always exhibits features of the condition; however, considerable intrafamilial phenotypic variability is observed in SMCD.…”